Snake Venom Metalloproteinase Containing a Disintegrin-like Domain, its Structure-activity Relationships at Interacting with Integrins

Abstract

Snake venom disintegrins represent a family of RGD (Arg-Gly-Asp) or KGD (Lys-Gly-Asp)-containing proteins which have been reported to be unique and potentially useful tools not only for investigating integrin-ligand interactions, but also for the development of anti-thrombotic agents in terms of their anti-platelet activities. Snake venom proteins containing a disintegrin-like domain represent another super-family of proteins in which many of them have been demonstrated to have similar ability to inhibit platelet aggregation and integrin-mediated cell adhesion as the disintegrins. This super-family includes a large number of snake venom metalloproteinases and disintegrin related, RGD-containing snake venom proteins (disintegrin-like proteins) such as dendroaspin. Recently, a family of homologues of the snake venom metalloproteinases have been found in a wide variety of mammalian tissues as well as in other eukaryotic organisms termed ADAM (a disintegrin-like and metalloproteinase) proteins. ADAMs are members of the metazincins that also include the related matrix metalloprotease (MMPs). Some of ADAM proteins have now shown to interact with integrins, and the disintegrin-like domain may be crucial part in their function as proteases. A description of structure-activity relationships of snake venom proteins containing a disintegrin-like domain is outlined in this review, along with reports of the modulation of protein activity by recombinant mutation. Comparison is also made of the structural and functional features of the metalloproteinases in snakes compared with those from other species. The review is intended to provide insights in which may assist the development of new therapeutic approaches.

NMRstructure of bitistatin – a missing piece in the evolutionary pathway of snake venom disintegrins

“…This indicated that the peak doubling did not affect the C-terminal region of the sequence. Similar observations were made from the natural abundance 13 C-HSQC spectrum (Fig. 2), which was particularly visible in the methyl group region, presenting many (but not all) replicated cross-peaks.…”

“…The full assignment of the backbone nitrogen atoms was possible for species B (= major species in 15 N-rbitistatin sample), whereas 86% of the nitrogen atoms were assigned for bitistatin A using natural abundance 15 N-spectra. Eighty-eight percent and 82% assignment was achieved for the Ca carbons of bitistatins A and B, respectively, via 13 C-HSQC spectra recorded with the natural abundance samples. Only a partial assignment (< 60% of the protons) was possible for minor bitistatin C. The NMR data confirmed that bitistatins A and B have identical primary structure, as well as the regions of bitistatin C that we were able to assign (residues 4-14 and 30-83).…”

“…The presence of PIII SVMPs in Viperidae (vipers and pit vipers) [12,13], Elapidae (cobras, kraits, Abbreviations ADAM, a disintegrin and metalloprotease; SVMP, snake venom metalloproteinase. coral snakes) [14], Colubridae (colubroid snakes) [15] and Atractaspididae (mole vipers, stiletto snakes) [16] supports the view that an early recruitment event of an ADAM gene predated the radiation of the advanced snakes (Caenophidia) [17] around the Cretaceous-Paleocene boundary, approximately 60 million years ago [18].…”

Animal toxins and the kidney

“…Metalloproteases in snake venom can cause proteolysis of the extracellular matrix and disrupt cell-matrix and cell-cell adhesion. 42 Integrins, which are critical for cellular adhesion, redistribute away from the basal surface of 16 Venom from snakes of the same genus as the Brazilian lancehead decreased neutral red uptake by Vero cells, another kidney epithelial cell line, indicating impairment of transmembrane transport. 44 In an experimental study, Russell's viper venom caused lysis of vascular smooth muscle cells, mesangiolysis and tubular degeneration with cellular detachment from the basement membrane.…”

Expression profiling, gene silencing and transcriptional networking of metzincin metalloproteases in the cattle tick, Rhipicephalus (Boophilus) microplus

“…Therefore, it can be hypothesized that silencing of the reprolysin and astacin metalloproteases (within the salivary glands and the midgut) could have indirectly impaired oogenesis by its effect on blood feeding and digestion (Lu et al, 2005;Jia et al, 1996;Sterchi et al, 2008). Since the astacin transcripts are also present in the ovaries and are known to be involved in vital functions such as growth factor activation (Stöcker et al, 1993) and embryo development (dorso-ventral patterning) (Shimell et al, 1991), thus a direct effect on oogenesis cannot be excluded.…”